Enhancement of Beta Cell Function with Pharmacologic and Sleep Apnea Treatment

通过药物和睡眠呼吸暂停治疗增强 β 细胞功能

基本信息

批准号：
8530646
负责人：
DAVID A EHRMANN
金额：
$ 55.12万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8530646
关键词：
Accounting Address Adult Affect African American Aftercare Agonist American Behavior Therapy Beta Cell Biological Preservation Body mass index Cell physiology Centers for Disease Control and Prevention (U.S.)Clinical Trials Comorbidity Continuous Positive Airway Pressure Critiques Development Diabetes Mellitus Diagnosis Dimensions Drug Combinations Epidemic Ethnic Origin Evaluation Face First Degree Relative Geographic Locations Gestational Diabetes Glucose Glucose Intolerance Goals Individual Infusion procedures Insulin Insulin Resistance Intervention Intravenous Inulin Laboratories Life Style Modality Modeling Monitor Non-Insulin-Dependent Diabetes Mellitus Not Hispanic or Latino OGTT Obesity Obstructive Sleep Apnea Oral Outcome Overweight Participant Pathogenesis Pattern Pharmaceutical Preparations Pharmacological Treatment Phase Pioglitazone Placebos Play Polycystic Ovary Syndrome Population Positioning Attribute Prediabetes syndrome Prevalence Prevention Published Comment Race Randomized Clinical Trials Recording of previous events Relative (related person)Risk Factors Role Sampling Sleep Sleep Apnea Syndromes Sleep Disorders Staging Structure of beta Cell of islet System Testing Wireless Technology Woman aged base clinical practice demographics design disorder prevention early onset experience glucagon like peptide glucagon-like peptide glucose tolerance improved innovation insulin secretion insulin sensitivity insulin sensitizing drugs intravenous glucose tolerance test liraglutide peer prevent response treatment response

项目摘要

DESCRIPTION (provided by applicant): Prevention of T2DM is a critical and attainable goal Interventions to prevent or delay development of T2DM in those with prediabetes have focused on reducing insulin resistance via lifestyle modification, the use of insulin lowering medications, or both. The introduction of incretin therapies, e.g., GLP agonists, makes it possible to determine if similar or superior outcomes can be achieved with strategies to preserve or enhance insulin secretion. The overall goal of this randomized clinical trial is to determine whether the expected augmentation in insulin secretion imparted by administration of liraglutide will be enhanced by the co-administration of pioglitazone, an insulin sensitizer that will "unburden the beta cell" and preserve beta cell function. This combination will be compared to liraglutide+placebo to determine whether the effects of pioglitazone, if any, are additive to or synergistic with those of liraglutide. A unique aspect of our approach is that, whenever applicable, CPAP treatment of OSA, an independent risk factor for insulin resistance, will be incorporated into the treatment paradigm and will serve as a covariate in the analysis of the response to pharmacologic therapy. All participants will be assessed at baseline and 26 wks post-treatment with: a 75gm 5-h OGTT analyzed by the modified minimal model, an isoglycemic glucose infusion to estimate the incretin effect, a fsIVGTT to estimate AIRg and Si, and a graded glucose infusion to assess beta cell function. We will target individuals with high rates of prediabetes and T2DM: adults with a first-degree relative with T2DM, women with a prior history of GDM, women with PCOS, and overweight and obese individuals aged >45 yr. The following Specific Aims will be addressed: Specific Aim 1. To determine if 26 wks of treatment with liraglutide+pioglitazone is superior to liraglutide+placebo in improving insulin secretion in individuals with prediabetes or recent-onset T2DM. Specific Aim 2: To determine if beta cell responsiveness to two different modalities of pharmacologic intervention (liraglutide alone and liraglutide+pioglitazone) is modulated by the presence of OSA and by African-American race/ethnicity. Specific Aim 3: To determine if treatment of OSA by CPAP preserves or enhances beta cell function in the absence of pharmacological treatment and if the impact of OSA on insulin secretion and action is modulated by race. Specific Aim 4: To determine if 26 wks of liraglutide+ pioglitazone is superior to liraglutide+placebo in extending the durability of drug treatment on beta cell function.

描述（由申请人提供）：预防 T2DM 是一个关键且可实现的目标对于糖尿病前期患者，预防或延缓 T2DM 发展的干预措施重点是通过改变生活方式、使用降胰岛素药物、或两者兼而有之。肠促胰岛素疗法（例如 GLP 激动剂）的引入使得确定通过保留或增强胰岛素分泌的策略是否可以实现类似或更好的结果成为可能。这项随机临床试验的总体目标是确定联合使用吡格列酮是否会增强利拉鲁肽给药所带来的胰岛素分泌预期增强，吡格列酮是一种胰岛素增敏剂，可以“减轻β细胞的负担”并保留β细胞功能。该组合将与利拉鲁肽+安慰剂进行比较，以确定吡格列酮的作用（如果有的话）是否与利拉鲁肽的作用相加或协同。我们方法的一个独特之处在于，只要适用，OSA（胰岛素抵抗的独立危险因素）的 CPAP 治疗将被纳入治疗范式中，并将作为药物治疗反应分析中的协变量。所有参与者将在基线和治疗后 26 周接受以下评估：通过改良的最小模型分析 75 克 5 小时 OGTT、等血糖葡萄糖输注以估计肠促胰素效应、fsIVGTT 以估计 AIRg 和 Si，以及分级葡萄糖输注以评估β细胞功能。我们将针对高比率的个人糖尿病前期和 T2DM：一级亲属患有 T2DM 的成年人、有 GDM 病史的女性、患有 PCOS 的女性以及年龄 > 45 岁的超重和肥胖个体。将解决以下具体目标：具体目标 1. 确定利拉鲁肽+吡格列酮 26 周治疗在改善糖尿病前期或新发 T2DM 个体的胰岛素分泌方面是否优于利拉鲁肽+安慰剂。具体目标 2：确定 β 细胞对两种不同药物干预方式（单独利拉鲁肽和利拉鲁肽+吡格列酮）的反应是否受到 OSA 的存在和非裔美国人种族/民族的调节。具体目标 3：确定在没有药物治疗的情况下，通过 CPAP 治疗 OSA 是否可以保留或增强 β 细胞功能，以及 OSA 对胰岛素分泌和作用的影响是否受到种族的调节。具体目标 4：确定 26 周的利拉鲁肽 + 吡格列酮在延长药物治疗对 β 细胞功能的持久性方面是否优于利拉鲁肽 + 安慰剂。